Immune or gamma-interferon was originally classified on a physical basis as Type II Interferon due to its lability to acid treatment and/or heating to 56.degree. C. This operational classification distinguished it from virus-induced or Type I Interferons (alpha and beta) which, in general, are not acid or heat labile. As a result of the widespread availability of specific antisera against each of the major interferon classes (alpha, beta, and gamma), classification and distinction of each type is now usually made by serological or immunological methods. Despite this, gamma-interferon preparations are still identified as such by their rapid inactivation upon acid treatment. See, The Interferon System, 2nd edition, W. E. Stewart II, Springer-Verlag, New York, 1981.
Gamma-interferon has been employed in clinical studies for many years. The methods currently available for preparing gamma-interferon dosage forms comprises lyophilizing the gamma-interferon in combination with other ingredients for reconstitution with an appropriate diluent at the time of use. Because gamma-interferon is known to be acid labile, it has traditionally been handled at neutral or slightly alkaline pH. See, for example, U.S. Pat. No. 4,499,014 which dicloses reactivation of a lyophilized acidic gamma-interferon solution to a pH of 6 to 9. U.K. Patent Application GB 2119313A discloses lyophilized formulations of gamma-interferon reconstituted at pH 7.5. Neutral or slightly alkaline solutions of higher concentrations of gamma-interferon are unusable as injectable formulations because of the immediate formation of a visible precipitate. Such precipitates may cause thrombosis on administration or decrease potency. European Patent Application Publication No. 0196203 discloses reconstitution of lyophilized gamma-interferon to a pH of 4 to 6.0.
An object of the present invention is to provide a biologically active, stable liquid formulation of gamma-interferon for use in injectable applications. Another object of this invention is to provide a formulation which does not require prior lyophilization of a gamma-interferon composition. It is another object of this invention to prevent dimer and oligomer formation consequent to lyophilization of gamma-interferon. Yet another object of this invention is to provide a liquid formulation containing biologically active gamma-interferon having improved stability. Still another object of this invention is to provide a liquid formulation permitting storage for a long period of time in a liquid state facilitating storage and shipping prior to administration. Still another object of this invention is to reduce aggregation of gamma-interferon, particularly that associated with heating. Another object of this invention is to provide a liquid formulation resistant to fluctuations in temperature. Yet another object of this invention is the elimination from the preparation of a bulking or stabilizing agent such as human serum albumin (HSA). Still another object of this invention is to reduce potential contamination by other proteins and other blood contaminants which may be associated with human serum albumin. Yet another object of this invention is to provide a liquid formulation which is easily made and administered having eliminated lyophilization and reconstitution steps. Yet another object of this invention is to provide a pharmaceutical composition containing non-lyophilized gamma interferon that can be produced less expensively.